Project 2: After marijuana, amphetamines are the most widely used illicit drug class woridwide and recent evidence shows that methamphetamine causes about 895 deaths per year in the U.S. and is responsible for an annual economic burden of $23.5 billion. Interoception comprises the sensing of the physiological condition of the body, consciously representing this internal state within the context of ongoing activities, and inifiating mofivated action to homeostatically regulate this state. Previous investigations have shown that individuals with insular lesions reported they had lost the urge to smoke, and our results indicate that attenuated activation in insula was related to an increase propensity to relapse. Although this links interoception to insular functioning abnormalities to drug addiction, the precise role of interoception in drug addiction is unclear. To test the hypothesis that dysregulated insular cortex function in amphetamine dependent (AD) individual results in an insufficient, instable, or non-adaptive adjustment to perturbations of the internal state, we will examine using event-related fMRI the neural processing of: (1) direct interoceptive stimulation during positively valenced and negatively valenced interoceptive stimuli, and (2) internally generated interoceptive stimulation using cue reactivity paradigms. The behavioral and brain response characteristics will be examined during: (a) anticipation, (b) stimulation, and (c) post-stimulus processing. The specific aims are: (1) To determine the status of the interocepfive system in response to positively and negatively valenced interoceptive sfimuli in adults with AD, adults in full sustained remission, and healthy comparison subjects; (2) To determine the sensifivity of the interoceptive system in response to internally generated interoceptive sfimulafion using cue reactivity in AD individuals, those in full sustained remission, and healthy comparison subjects; (3) To modify the neuroimaging paradigms in response to the animal studies (Project 3) and results from Wave 1 human studies to determine whether negafive or positively valenced interocepfive stimulation modulates cue reactivity in AD individuals at various stages of drug use. The clarification of the role of interocepfion and insular cortex functioning in various stages of amphetamine dependence would help to identify a vulnerability window when individuals are at high risk for relapse. Determining whether there is an altered valence-specific sensitivity of the interoceptive system in AD would help to select specific sfimulus materials for cognitive and emotional intervention approaches. Elucidafing the relationship betiA/een interoceptive dysfunctions and other psychological constructs, e.g. craving and selfefficacy, will help to relate interoception to existing theories of drug addiction.